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Title: Nano-engineered materials to probe and affect natural killer cell function
Author: Loftus, Christian
ISNI:       0000 0004 9350 3458
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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The nanoscale biological structures and dynamics that occur within cells have slowly been recognized as important features that determine cellular function. In the field of Immunology the receptors which determine a cell's response have recently been observed to organize on the nanoscale, forming clusters which vary in size, shape, and density. While these supramolecular structures have been observed, their function is still unknown, and current methods used to discern their function could be improved. Here, biomaterials with spatially controlled nanoscale features have been produced and developed with this goal in mind. Engineered nanomaterials have advantages over many biological techniques, especially in nanoscale manipulation and reduced experimental complexity. In this thesis two new nanoscale biomaterial approaches are developed, focusing on controlling the nanoscale spatial presentation of ligands to Natural Killer (NK) cells. The first is the fabrication of a supramolecular reagent which clusters Monoclonal Antibodies (mAbs) using a Nanoscale Graphene Oxide (NGO) framework. These clusters are on the same scale and density as receptor nanoclusters and exhibit properties that better mimic natural receptor ligation---such as interconnected ligands and local ligand density. Nanoscale Graphene Oxide-Monoclonal Antibody (NGO-mAb) species were found to augment degranulation and cytokine secretion of primary (human) NK (pNK) cells in comparison to equivalent concentrations of unclustered mAbs. Secondly, gold nanoparticle arrays, a nanotechnology used to create mimetic cell surfaces with nanometer control of ligand spacing, were imaged with Stochastic Optical Reconstruction Microscopy (STORM), a single molecule localization technique, to characterize their biological functionalization. This characterization step is necessary to confirm the nanoscale patterning, but remains difficult, and new methods for its accurate measurement are needed. Results obtained indicate that in spite of measured underoccupation, regions could be discerned as having spatial properties and patterning that would be expected of a functionalized array by three independent analytical methods.
Supervisor: Dunlop, Iain ; Davis, Daniel Sponsor: Engineering and Physical Sciences Research Council ; Medical Research Council ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral